Self assessment of therapeutic results from patients with implanted drug delivery systems for pain and spasticity therapy indicate that efficacy varies from poor to excellent. While there are a number of factors that may contribute to this variation, at least some of this disparity may be due to variability in the amount of drug that actually reaches the intended pain receptors. Stated alternatively, when the delivered drugs reach the intended receptors, it is believed that more effective therapy results. When the delivered drugs are unable to reach the intended receptors, or are otherwise substantially diluted by the time they reach the intended receptors, therapeutic effects may be diminished.
Further aggravating this problem is the fact that drugs that do not reach the desired receptors may migrate to yet other receptors, potentially resulting in unintended and undesirable side effects. Such side effects may necessitate a reduction in the overall drug dosage that the patient may safely tolerate.
To treat pain and/or spasticity, therapeutic drugs are often infused, or otherwise delivered, into cerebrospinal fluid (CSF) contained within an intrathecal space surrounding the spinal cord. The drug may then distribute through the CSF, whereby at least some of the drug is intended to reach the target receptors.
While effective, distribution of drugs through CSF is complex and is not well understood. For example, drug distribution mechanisms through CSF may include: diffusion through the CSF; diffusion into the spinal cord and epidural space, then diffusion through the tissues; natural CSF convection (CSF convection may result from production and uptake processes, arterial expansion from cardiac cycle, tissue displacement during the respiratory cycle, tissue displacement during body motion, etc.); mixing of the drug in CSF due to movement around spinal structures; and buoyancy due to differences in density. These factors make it difficult to predict what infusion characteristics will yield the greatest efficacy. Compounding this problem is the fact that clinicians are often unable to effectively improve therapy for those patients who initially report poor results.
It is difficult to directly measure the amount of drug that reaches the desired receptors within the spinal cord, or even to determine an approximate drug distribution within CSF. For example, in humans, CSF samples are generally only taken below the cauda equina or in the cistema magna to avoid damaging the spinal cord with the sampling needle. As a result, drug presence at receptors located at specific locations along the spinal cord is difficult to quantify.
Further, drugs introduced into CSF are not easily imaged via non-invasive methods. Rather, as drug concentration in CSF is low, a marker or contrast agent is generally required for accurate detection. However, markers pose a potential risk of neurotoxicity. In fact, only one marker, 111In-DTPA, is approved and labeled for use in the central nervous system (CNS) by the U.S. Food and Drug Administration. While 111In-DTPA may be detected with nuclear imaging cameras, it is also much heavier than many neurological drugs and thus may not distribute within CSF in the same manner.
Still further, while small and large animal models have been used to study drug distribution within the spine, such animals do not have a spinal anatomy that is similar to humans, primarily because these animals do not walk, stand, and sit upright. Thus, such animal studies are not believed to provide an accurate prediction of drug distribution in humans.